This is a revised submission of our developmental grant (R21) proposing to study the association between immunophilins (IP) and markers of neurodegeneration in HIV infected patients and test the hypothesis that IP ligand (IPL) treatments may protect against HIV-associated axonal degeneration mediated by chemokines. We will characterize the normal and pathologic distribution of the FKBP family of IP in autopsy brain tissues from HIV infected patients with cognitive impairment and controls. We will also use an in vitro experimental model based on human brain cell cultures to study the association between IP and the presynaptic apparatus and analyze the effects of IPL treatments on neuronal survival and differentiation in the presence of HIV infection and glial activation. Our understanding of the role played by immunophilins in response to chronic neuronal injury in the HIV infected brain may lead to identifying new early markers of disease. Furthermore, IP may represent excellent targets for therapeutic interventions. Current studies suggest that IP ligands are potent neuroprotective agents and some of them are already in clinical use. Project Summary We plan to study the function of a relatively new family of abundant brain proteins, called immunophilins (IP), that may be involved in the survival and normal function of neurons in HIV infected patients. Our understanding of the role played by immunophilins in response to chronic neuronal injury may lead to the early diagnosis of neuropsychiatric damage and potential therapeutic interventions in long term survivors with HIV. Current studies suggest that IP ligands are neuroprotective and some of them are already in clinical use in organ transplant patients. [unreadable] [unreadable] [unreadable]